It is springtime, how nice! You see colorful flowers, birds singing, trees blooming… oh no! That also means dreaded pollen is flying in the air. Allergy season is here! When we hear about allergies, we think of this kind of seasonal allergy to environmental substances. However, this is not the only allergy people can develop. Many people suffer from allergies to a lot of other substances, including food, drugs, cosmetics, creams and fragrances. Allergies occur when our immune system is “too” sensitive (hypersensitive) to those substances. However, how exactly the immune system recognizes and reacts to different kinds of allergens varies and is not fully understood. Nicolai and colleagues went deeper into understanding how our immune system recognizes contact substances, including creams and cosmetics.

How are allergies produced?

Our immune system performs a dual job. While it efficiently fights and eliminates pathogens, it also tolerates everyday antigens (molecules that you encounter often) and self-antigens (molecules produced by our own cells). The balance between fighting pathogens and tolerating substances follows very fine-tuned processes. Our immune system is armed with many different types of cells that each have their own specific role to play. One important cell is the T cell (a type of white blood cell), which is important both in fighting pathogens and tolerating everyday substances. T cells react to very specific substances called antigens or in the case of allergies, allergens. For example, a T cell may recognize a specific molecule from bacteria. This triggers the T cell to “turn on” and work to get rid of the invading bacteria. This process also occurs when the body encounters an environmental substance or self-antigens. However, in this case the T cell is attacking either an everyday antigen or self-antigens, which would not be beneficial for us. Therefore, there are systems in place to control the activation of these T cells so that they do not attack everyday environmental substances or your own body. These T cells that react to our own cells are eliminated, producing tolerance. Allergies happen when tolerance from our immune system fails.

Allergies are triggered by hypersensitive T cells, which were not controlled or eliminated. T cells recognize an allergen through their most important molecule, the T cell receptor or TCR, which sits on the cell’s surface. But the allergen does not just come alone to the TCR, it needs to be presented by specific cells called antigen presenting cells (APCs), such as macrophages or dendritic cells. The APCs have a molecule on their surface called Major Histocompatibility Complex I or II (MHC) on which the allergen is presented like a crown on a cushion (Figure 1). The crown, a.k.a allergen, needs to be processed (cut in pieces) before being presented. When in pieces, the T cell can recognize the allergen and respond to it, producing the allergy symptoms so many of us are familiar with, like rash, for example.

The MHC molecule can present mainly proteins (a bunch of peptides) to T cells. Most contact (skin) allergens are not proteins, but smaller molecules like oils or metals, which are found in creams, toothpastes and cosmetics. Therefore, the way they are presented is slightly different. The mechanism behind how skin allergens are processed and recognized had not been previously understood. To test which mechanism is used for oily allergens, scientists at Columbia University Vagelos College of Physicians, Harvard Medical School in the USA and Monash University in Australia used a combination of common allergic patches, cells and biochemistry, and published their results in Science Immunology journal. Their results shed some light on this process, finding that MHC is not involved, instead another unconventional molecule called CD1 is used to present oily allergens to T cells.

Oily allergen presentation

Allergies are diagnosed by physicians by applying allergen patches, which contain embedded allergens, to the skin and then measuring local skin inflammation. Nicolai and colleagues screened important allergens present in skin patch testing kits. From all compounds contained in these patches, the authors found that T cells respond strongly to tree oils that are present as fragrances or additives in creams, cosmetics and toothpastes. These compounds were farnesol, coenzyme Q2, benzyl benzoate and benzyl cinnamate. These two latter compounds were the most abundant components in balsam of Peru. (yes, I also went to see my shampoo and cream labels in the bathroom and they contain some of these!). All these compounds share similar chemical characteristics: small size, highly hydrophobic (do not like water) and special structure in the form of rings or multiple bonds (unions).

The authors found that these oils are recognized by T cells not through MHC but a similar molecule, called CD1a, and without being cut (Figure 2). CD1 is an abundant protein found in APCs in human skin and is chemically similar to MHC I. Although CD1a, b, c and d exist, CD1a was shown to activate the T cells better. How is it possible that T cells can recognize these oils?  The scientists found that the tree oils, because of their chemical nature (small size, ring form, etc), displace self-fats that are not touching the TCR directly or bound strongly to CD1a. After the displacement, the oils touch the TCR and this induces a response.

Do only allergic people have CD1a?

No, every person has CD1a, and the skin contains a big amount of this molecule but not everybody reacts to tree oils, possibly because each person’s skin has different properties to absorb components (creams, perfumes). It could be also because of differences in our immune cells, including our T cells. Not all our T cells respond to the same allergen and not all allergens trigger a response in one T cell, providing us a T cell collection. This means that a diverse population of T cells exist in us, with each cell specific for one allergen. However, CD1a reacting T cells specific for these oily components can be found in higher numbers in people who suffer contact dermatitis (red, itchy rash caused by direct contact with a compound) than in people who don’t. That means that the amount of specific T cells is the key.

So, every time after using a cream, which contains oily compounds, you get a rash, you should blame your CD1a molecule hypersensitivity on T cells!

Journal article: S. Nicolai, et al. Human T cell response to CD1a and contact dermatitis allergens in botanical extracts and commercial skin care products. Science Immunology 2020, Vol. 5, Issue 43, eaax5430, https://immunology.sciencemag.org/content/5/43/eaax5430.long

Figures generated in BioRender

Cover image: cream, CC BY-ND